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3
Chlorobenzene1
Acute Exposure Guideline Levels
PREFACE
Under the authority of the Federal Advisory Committee Act (FACA) P.L.
92-463 of 1972, the National Advisory Committee for Acute Exposure Guide-
line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab-
lished to identify, review, and interpret relevant toxicologic and other scientific
data and develop AEGLs for high-priority, acutely toxic chemicals.
AEGLs represent threshold exposure limits for the general public and are
applicable to emergency exposure periods ranging from 10 minutes (min) to 8
hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for
each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin-
guished by varying degrees of severity of toxic effects. The three AEGLs are
defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million or
milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is
predicted that the general population, including susceptible individuals, could
experience notable discomfort, irritation, or certain asymptomatic, nonsensory
1
This document was prepared by the AEGL Development Team composed of J.J.A.
Muller and Peter Bos (both from RIVM, The Dutch National Institute of Public Health
and the Environment), Julie M. Klotzbach (Syracuse Research Corporation), Chemical
Manager Marinelle Payton (National Advisory Committee [NAC] on Acute Exposure
Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental
Protection Agency). The NAC reviewed and revised the document and AEGLs as
deemed necessary. Both the document and the AEGL values were then reviewed by the
National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The
NRC committee has concluded that the AEGLs developed in this document are scientifi-
cally valid conclusions based on the data reviewed by the NRC and are consistent with
the NRC guidelines reports (NRC 1993, 2001).
82
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Chlorobenzene
effects. However, the effects are not disabling and are transient and reversible
upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a
substance above which it is predicted that the general population, including sus-
ceptible individuals, could experience irreversible or other serious, long-lasting
adverse health effects or an impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a
substance above which it is predicted that the general population, including sus-
ceptible individuals, could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure concentra-
tions that could produce mild and progressively increasing but transient and
nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen-
sory effects. With increasing airborne concentrations above each AEGL, there is
a progressive increase in the likelihood of occurrence and the severity of effects
described for each corresponding AEGL. Although the AEGL values represent
threshold concentrations for the general public, including susceptible subpopula-
tions, such as infants, children, the elderly, persons with asthma, and those with
other illnesses, it is recognized that individuals, subject to idiosyncratic re-
sponses, could experience the effects described at concentrations below the cor-
responding AEGL.
SUMMARY
Chlorobenzene is a flammable liquid with a high vapor pressure and a wa-
ter solubility of 50 milligrams per liter (mg/L) at 20°C. It is used as a solvent
and in the production of nitrochlorobenzene and intermediates for the synthesis
of dyestuffs, pharmaceuticals, and products for the rubber and plastic industries.
Chlorobenzene has an aromatic, almond-like odor. The odor threshold is 0.050
mg/L in water and is 0.2-1.8 ppm in air, although a value of 62 ppm has also
been reported for air.
The toxicity database on chlorobenzene is poor. Information often had to
be obtained from descriptions in reviews and summaries, and some older litera-
ture could not be obtained (e.g., Rozenbaum et al. [1947]). Human data include
to two kinetic studies with volunteers. Animal data included studies on terato-
genicity, reproductive toxicity, and mortality. A few studies with experimental
animals addressing central nervous system (CNS) depression were reviewed, but
were difficult to interpret.
AEGL-1 values are based on kinetic studies with volunteers. Effects in
subjects exposed to chlorobenzene at 60 ppm for 7 h (with a 1-h break after 3 h)
are indicative of slight CNS depression (drowsiness, heavy head, and headache)
and local irritation (Ogata et al. 1991), and are considered evidence of discom-
fort. These effects were not observed is subjects exposed at 10 ppm for 8 h
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84 Acute Exposure Guideline Levels
(Knecht and Woitowitz 2000). Thus, 10 ppm was chosen as a conservative point
of departure for the derivation of AEGL-1 values. Because human data are used,
an interspecies uncertainty factor of 1 was used. Despite the fact that only a few
subjects were tested, an uncertainty factor of 1 for intraspecies variability was
considered appropriate because of the conservatism of the point of departure
already provides a margin of safety. (The point of departure of 10 ppm was ob-
tained from a repeated-exposure study, and effects observed at 60 ppm were
rather slight.) No information about the time dependency of the effects at 10 or
60 ppm is available. Because the effects at 60 ppm include irritation and CNS
effects, the 8-h AEGL-1 value of 10 ppm is considered appropriate for all time
points. Furthermore, Knecht and Woitowitz (2000) reported that chlorobenzene
concentrations in blood reached a steady-state level within 1 h.
There are no adequate human data for deriving AEGL-2 values. Some
studies with experimental animals report subtle CNS effects, but the relevance
of these effects to humans is difficult to interpret. The effects reported by Fran-
tik et al. (1994) and De Ceaurriz et al. (1983) are considered effects below those
defined by AEGL-2. A more appropriate study is the one by UBTL (1978), in
which rats and guinea pigs experienced narcosis and effects that would impair
ability to escape. A no-effect concentration of 2,990 ppm for 30 min was se-
lected as the point of departure for calculating AEGL-2 values. An interspecies
uncertainty factor of 3 was applied, because data were comparable for rats and
guinea pigs, suggesting no large interspecies differences, and the critical effect
is CNS depression. The concentration of chlorobenzene in the brain is probably
related directly to inhalation rate. Therefore, humans probably require higher
external exposures than rodents to obtain a similar concentration of chloroben-
zene in the blood or brain. Experience with anesthetic gases shows that interin-
dividual variability in CNS depression caused by these gases is generally not
greater than a factor of 2 or 3. Therefore, an intraspecies uncertainty factor of 3
was used. A combined uncertainty factor of 10 was considered appropriate be-
cause a larger factor would result in AEGL-2 values below 60 ppm, which a
concentration shown to cause only minor effects in humans. The 30-min AEGL-
2 was 300 ppm. The 30-min value was extrapolated to 10-min and 1-h values
using the equation Cn × t = k, with default values of n = 1 for extrapolation to 1
h and n = 3 for extrapolation to 10 min. The 4- and 8-h AEGL-2 values were set
equal to the 1-h value because chlorobenzene concentrations in blood reach a
steady-state within 1 h and elimination is rapid. Furthermore, time scaling would
result in 4- and 8-h AEGL-2 values that conflict with human data (Ogata et al.
1991).
For the derivation of AEGL-3 values, several mortality studies were
found, but most were only available as summaries in other publications and
could not be judged on their merits. Bonnet et al. (1979, 1982) reported a 6-h
LC50 (lethal concentration, 50% lethality) of 2,965 ppm for male rats and a 6-h
LC50 of 1,886 ppm for mice. No deaths were reported in rats or guinea pigs ex-
posed to chlorobenzene at concentrations of up to 7,970 ppm for 30 min (UBTL
1978). Data in rats and guinea pigs reported by UBTL (1978) provide the most
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Chlorobenzene
appropriate point of departure for AEGL-3 derivation. A total uncertainty factor
of 10 was applied on the same basis it was applied in the derivation of the
AEGL-2 values, and time scaling was performed the same as was done for the
AEGL-2 values. AEGL-3 values are consistent with the AEGL-2 values and are
supported by the 6-h LC01 of 1,873 ppm calculated from the probit equation re-
ported by Bonnet et al. (1982). AEGL values for chlorobenzene are presented in
Table 3-1.
1. INTRODUCTION
Chlorobenzene is a flammable liquid with a high vapor pressure and a wa-
ter solubility of 50 mg/L at 20°C. It is commercially produced by the chlorina-
tion of benzene in the presence of a catalyst (ATSDR 1990). Chlorobenzene is
used as a solvent and in the production of nitrochlorobenzene and intermediates
for the synthesis of dyestuffs, pharmaceuticals, and products for the rubber and
plastic industries (BUA 1990). The production volume of chlorobenzene in 1992
was 231 million pounds in the United States (EPA 1995). More current informa-
tion on production volumes was not available.
Chlorobenzene has an aromatic, almond-like odor. The odor threshold for
chlorobenzene in water is 0.050 mg/L and in air is 0.2-1.8 ppm (Verschueren
1983). Odor thresholds for chlorobenzene have been reported as low as 0.2 ppm
and as high as 62 ppm (Ruth 1986). Chemical and physical properties for
chlorobenzene are presented in Table 3-2.
2. HUMAN TOXICITY DATA
2.1. Acute Lethality
No data were available.
TABLE 3-1 Summary of AEGL Values for Chlorobenzene
End Point
Classification 10 min 30 min 1h 4h 8h (Reference)
AEGL-1 10 ppm 10 ppm 10 ppm 10 ppm 10 ppm No irritant or CNS
(nondisabling) (47 (47 (47 (47 (47 effects (Ogata et al.
mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) 1991; Knecht and
Woitowitz 2000)
AEGL-2 430 ppm 300 ppm 150 ppm 150 ppm 150 ppm Narcosis (UBTL
(disabling) (2,021 (1,410 (705 (705 (705 1978)
mg/m3) mg/m3) mg/m3) mg/m3) mg/m3)
AEGL-3 1,100 ppm 800 ppm 400 ppm 400 ppm 400 ppm No mortality in
(lethal) (5,170 (3,760 (1,880 (1,880 (1,880 rats or guinea pigs
mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (UBTL 1978)
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86 Acute Exposure Guideline Levels
TABLE 3-2 Chemical and Physical Properties for Chlorobenzene
Parameter Value Reference
CAS registry no. 108-90-7
Synonyms Monochlorobenzene; benzene
chloride; phenylchloride; MCB;
chlorobenzol
Chemical formula C6H5Cl
Molecular weight 112.56
Physical state Liquid ATSDR 1990
Color Colorless ATSDR 1990
Odor Aromatic, almond-like ATSDR 1990
Melting point -45.6°C ATSDR 1990
Boiling point 132°C ATSDR 1990
3
Liquid density (water = 1) 1.1058 g/cm ATSDR 1990
Solubility in water 500 mg/L at 20°C ATSDR 1990
Vapor pressure 8.8 mm Hg at 20°C ATSDR 1990
Flammability 1.8-9.6% ATSDR 1990
Lower explosive limit 1.3% NIOSH 2011
3
Conversion factors 1 mg/m = 0.22 ppm ATSDR 1990
1 ppm = 4.7 mg/m3
2.2. Nonlethal Toxicity
2.2.1. Case Reports
Several reviews including those of ACGIH (1991) and Hellman (1993)
cited reports in which inhalation and oral exposure to chlorobenzene are de-
scribed as having caused drowsiness, incoordination, and unconsciousness, as
well as irritation of the eyes and respiratory tract. However, exposure concentra-
tions were not specified.
Ruth (1986) reported that 205 ppm was an irritating concentration of
chlorobenzene, but the source of that information was not provided.
2.2.2. Experimental Studies
In a study investigating urinary metabolites of chlorobenzene, subjects
were asked to report subjective effects of the exposure (Ogata et al. 1991). Vol-
unteers were exposed to chlorobenzene at 60.2 ± 3.9 ppm for 3 h in the morning
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Chlorobenzene
and 4 h in the afternoon, with a 1-h break between exposures. The concentra-
tions were determined by gas chromatography and were reported to be constant
within a 5% range. All of the volunteers complained of a disagreeable odor and
drowsiness. Three had a heavy feeling in the head or headache, two had a throb-
bing pain in the eyes, and one had a sore throat. No information was given about
the onset of these complaints. Chlorobenzene did not affect pulse rates or sys-
tolic and diastolic pressure. Flicker fusion frequency values (frequency at which
successive flashes are seen as continuous) were reduced significantly from 39.1
to 35.9 cycles/second at the end of the 3-h exposure. No further effect was seen
in the afternoon. The significance of this finding is difficult to interpret.
Eight volunteers were exposed to chlorobenzene at 10 ppm for 8 h per day
for five consecutive days to determine the relationship between chlorobenzene
and urinary concentrations of its metabolites 4-chlorocatechol and chlorophenols
(Knecht and Woitowitz 2000). None of the subjects complained of irritant or
CNS effects (U. Knecht, Justus Liebig University Giessen, Germany, personal
commun., 2005).
2.2.3. Occupational and Epidemiologic Studies
The potential consequences of occupational exposure to chlorobenzene are
described in a report by Izmerov et al. (1988). These cases are not included in
the chapter because concentrations of chlorobenzene in those studies were un-
clear and coexposure to other chemicals was possible.
2.3. Neurotoxicity
Izmerov et al. (1988) described changes in electroencephalogram (EEG)
readings as “evident on an individual basis” during exposure to chlorobenzene
and as near-term and long-term effects. The specific changes were not de-
scribed. On the basis of changes in electrical brain activity, 0.2 mg/m3 (0.044
ppm) appeared to be a threshold concentration (exposure duration unknown),
and 0.1 mg/m3 (0.022 ppm) was a no-effect concentration. No further details
were provided in the Izmerov report, and the original publications were not
available. Therefore, these results are considered supplementary information.
2.4. Summary
No information is available on the acute lethality of chlorobenzene in hu-
mans. Chlorobenzene can be irritating to the eyes and respiratory tract, and signs
of CNS effects (drowsiness, heavy feeling in the head, and headache) have been
report in people exposed at 60 ppm for 7 h. Odor might have interfered with
subjective complaints of irritation. No complaints of irritation were described in
another study in which volunteer were exposed to chlorobenzene at 10 ppm for
8 h/day for 5 days.
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88 Acute Exposure Guideline Levels
3. ANIMAL TOXICITY DATA
3.1. Acute Lethality
The acute lethality data on chlorobenzene in laboratory animals is pre-
sented in Table 3-3.
TABLE 3-3 Acute Lethality Data on Chlorobenzene in Laboratory Animals
Concentration Exposure
Species (sex) Effect Reference
(ppm) Duration
Single exposure
Rats (male) 2,965 6h LC50 Bonnet et al. 1982
Rats (or mice) 4,400 2h LC100 Rozenbaum et
al. 1947
Guinea pigs 7,970 30 min No mortality UBTL 1978
Rats 22,000 3.5 h 2 of 3 died Eastman Kodak
Co. 1994
Rats 9,000 6h 2 of 3 died Eastman Kodak
Co. 1994
Rats 7,970 30 min No mortality UBTL 1978
Mice (female) 1,886 6h LC50 Bonnet et al. 1979
Mice 7,832 2h LC84 Sanotsky and
Ulanova 1975
4,070 2h LC50
2,244 2h LC16
Related exposures
Rat (two- 450 6 h/d, 7 d/wk No mortality Nair et al. 1987
generation study) for up to 17 wk
Rabbits (pregnant) 3,000 6 h/d for 13 d Mortality John et al. 1984
1,000 No mortality
Rats (pregnant) 3,000 6 h/d for 10 d Mortality John et al. 1984
1,000 No mortality
Rats 248 7 h/d, 5 d/wk No mortality Dilley 1977
for 24 wk
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Chlorobenzene
3.1.1. Rabbits
A description of a study by Rozenbaum et al. (1947) was obtained from a
report by ATSDR (1990), because the original publication could not be ob-
tained. Rabbits (sex and number not specified) exposed to chlorobenzene (head
only or whole body) at 550-660 ppm for 4 h died after 2 weeks, but no effects
were observed at 110-220 ppm. Rabbits were also reported to have died 2 weeks
after exposure to chlorobenzene at 537 ppm for 2 h. These results contrast with
findings in other studies. For example, repeated exposure of 32 male rabbits to
chlorobenzene at 248 ppm for up to 24 weeks did not increase mortality (Dilley
1977). In addition, no mortality was observed in a teratogenicity study of rabbits
exposed at 1,000 ppm (6 h/day for 10 days), but deaths were observed at 3,000
ppm (John et al. 1984) (see Section 3.3 for further details of this study).
3.1.2. Guinea Pigs
Groups of five guinea pigs per sex were exposed (whole body) to chloro-
benzene at mean (± standard deviation [SD]) analytic concentrations of 2,990 ±
53, 5,850 ± 1,350, or 7,970 ± 355 ppm for 30 min, and were observed for 14
days. No deaths were observed at any concentration (UBTL 1978).
3.1.3. Rats
Bonnet et al. (1982) determined the 6-h LC50 for chlorobenzene in male
Sprague-Dawley rats. Twelve rats per concentration were exposed (whole body)
and observed for 14 days. Nominal test concentrations were not provided. Ac-
tual concentrations were determined using gas chromatography, but information
on the exposure concentrations was limited to a graph on log scale. It was esti-
mated that the lowest concentration tested in rats was approximately 2,000 ppm
and was associated with 8% mortality. The LC50 was 2,965 ppm (95% confi-
dence interval [CI]: 2,787-3,169 ppm), with a regression line of probit = -33 +
10.9 logC (the paper presented a positive intercept [+33] but the data indicate
that it should be -33). Hypotony, stereotypy, somnolence, tremor, and muscle
contractions were observed during exposure.
A 2-h LC100 value of 4,400 ppm for rats was determined by Rozenbaum et
al. (1947, as reported by BUA 1990). However, according to ATSDR (1990),
this study was performed in mice. The original publication could not be re-
trieved to clarify the discrepancy.
The following statement was found in a submission to the U.S. Environ-
mental Protection Agency (Eastman Kodak Co 1994): “Acute exposure to
22,000 ppm for 3½ h killed 2/3 rats in 2½ h while 9,000 ppm for 6 h killed 2/3
rats in 3 h.” A reference to unpublished data from the Eastman Kodak Company
was cited, but the original study was not available.
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90 Acute Exposure Guideline Levels
Groups of five rats per sex were exposed (whole body) to chlorobenzene
at mean (± SD) analytic concentrations of 2,990 ± 53, 5,850 ± 1,350, or 7,970 ±
355 ppm for 30 min, and animals were observed for 14 days. No deaths were
observed at any concentration (UBTL 1978).
Repeated exposure of 32 male rats to chlorobenzene at 248 ppm for up to
24 weeks did not result in mortality (Dilley 1977). In addition, no mortality was
observed in a two-generation study (450 ppm, 6 h/day, 7 days/week for 17
weeks) (Nair et al. 1987) or in a rat developmental toxicity study (1,000 ppm,
6 h/day for 10 days) (John et al. 1984). However, in the latter study, increased
mortality was observed at 3,000 ppm (John et al. 1984).
3.1.4. Mice
Bonnet et al. (1979) determined the 6-h LC50 of chlorobenzene in female
mice (OF1). Groups of 25 mice were exposed to chlorobenzene (whole body)
and observed for 14 days. Nominal test concentrations were not provided. Ac-
tual concentrations were determined using gas chromatography. The analytic
concentrations were 90-100% of the nominal concentrations. No details on the
exposure concentrations were provided other than a graph on log scale. It was
estimated that the lowest concentration tested was approximately 1,500 ppm and
caused approximately 20% mortality. The LC50 was 1,886 ppm (95% CI: 1,781
-1,980 ppm), with a regression line of probit = -17.06 + 6.734 logC (the paper
presented a positive intercept [+17.06] but the data indicate that it should be
-17.06).
Izmerov et al. (1988) described a study by Sanotsky and Ulanova (1975)
that found a 2-h LC50 of 4,070 ppm, an LC16 of 2,244 ppm, and an LC84 of 7,832
ppm for chlorobenzene in mice. Izmerov also reported that another study re-
ported that exposure to chlorobenzene at 2,200 ppm (duration unknown) failed
to kill mice, but that at 4,400 ppm three of four mice died. Neither of the pri-
mary studies could be obtained.
A 2-h LC100 value of 4,400 ppm for mice was reported by Rozenbaum et
al. (1947, as cited by ATSDR 1990). However, according to BUA (1990), this
study was performed in rats. The original publication could not be retrieved to
clarify the discrepancy.
3.2. Nonlethal Toxicity
The acute nonlethal effects of chlorobenzene in laboratory animals are
summarized in Table 3-4.
3.2.1. Guinea Pigs
Groups of five guinea pigs per sex were exposed (whole body) to chloro-
benzene at mean (± SD) analytic concentrations of 2,990 ± 53, 5,850 ± 1,350, or
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Chlorobenzene
7,970 ± 355 ppm for 30 min, and were observed for 14 days. No deaths were
observed at any concentration. At 2,990 ppm, slight ocular and nasal irritation
was observed, but none of the animals were judged to have an impaired ability
to escape. At the next higher concentration of 5,850 ppm, all guinea pigs suf-
fered from narcosis and were judged to have impaired ability to escape. No
deaths occurred at the highest concentration but ataxia occurred within 10 min
and narcosis was evident after 15 min (UBTL 1978).
TABLE 3-4 Acute Nonlethal Effects of Chlorobenzene in Laboratory Animals
Species Concentration Exposure
(sex) (ppm) Duration Effect Reference
Guinea pigs 2,990 30 min Slight ocular and nasal UBTL 1978
irritation; no impaired
ability to escape.
5,850 30 min Narcosis in all guinea pigs.
7,970 30 min Ataxia within 10 min and
narcosis within 15 min.
Rats 2,990 30 min Slight ocular and nasal UBTL 1978
irritation; no impaired ability
to escape.
5,850 30 min Narcosis in most rats.
7,970 30 min Ataxia at 10 min and narcosis
within 25 min.
Rats (male) 1,500 8 h/d for Reduction in auditory-evoked Rebert et al. 1995
5d response.
1,000 No effect.
Rats (male) 611 4h Shortening of the tonic Frantik et al. 1994
extension of the hind limbs
by 37.5% after electrical
stimulation.
Mice (male) 1,054 5 min RD50 for sensory irritation. De Ceaurriz et
al. 1981
Mice 75 3 h, once No effect on host defense. Aranyi et al. 1986
or for 5 d
Mice (female) 610 2h Increased velocity of the tonic Frantik et al. 1994
extension of the hind limbs by
30% after electrical stimulation.
Mice (male) 650 4h Decrease in immobility in De Ceaurriz et
the “behavioral despair” al. 1983
swimming test by 2.
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92 Acute Exposure Guideline Levels
3.2.2. Rats
Groups of five rats per sex were exposed (whole body) to chlorobenzene
at mean (± SD) analytic concentrations of 2,990 ± 53, 5,850 ± 1,350, or 7,970 ±
355 ppm for 30 min, and were observed for 14 days. No deaths were observed at
any concentration. At 2,990 ppm, slight ocular and nasal irritation was observed
but none of the animals were judged to suffer from impaired ability to escape.
At the next higher concentration of 5,850 ppm, most rats suffered from “narco-
sis” and were judged to have impaired ability to escape; the animals recovered
quickly after exposure ended. No deaths occurred at the highest concentration,
but ataxia was present at 10 min and narcosis was evident in all animals after 25
min of exposure (UBTL 1978).
Frantik et al. (1994) investigated the relative neurotoxicity of several sol-
vents. Groups of four adult male rats (albino, specific pathogen free) were ex-
posed at least three concentrations of chlorobenzene (analytic purity) or to am-
bient air. Inhalation exposure was performed in a dynamic system for 4 h, and
concentrations were measured by gas chromatography. The actual exposure
concentrations were not specified. Most animals were tested three or four times
at intervals of 3 weeks. Immediately after exposure, the animals received a short
electrical pulse through ear electrodes. The duration of subsequent tonic exten-
sion of the hind limbs was determined. This parameter was shown to be the most
sensitive and consistent. The study authors calculated the concentration required
to induce a 37.5% change in the neurologic response (decrease in duration of the
tonic extension from 8 to 5 seconds). A 37.5%-effect concentration of 611 ppm
(90% CI: 538-684 ppm) was reported for chlorobenzene. The slope was
0.061%/ppm. A 37.5% response corresponds, according to the study authors, to
a concentration that does not influence normal locomotor activity or induce be-
havioral excitation, so it may be considered a sensitive neurologic end point.
Rebert et al. (1995) studied the effect of chlorobenzene on the auditory
system of rats. Groups of eight or nine male Long Evans rats were exposed (whole
body) at target concentrations of chlorobenzene of 500-2,400 ppm for 8 h per day
for 5 days. Analytic concentrations determined by gas chromatography were
within 10% of the target concentrations. Auditory function was assessed 3-13 days
after exposure using the brainstem auditory-evoked response (integrated ampli-
tude) elicited by 16-kilohertz (kHz) tone pips over a range of 25-95 decibels (dB),
with 10 dB increments. The average response over 55-85 dB was compared with
controls. A reduction in the integrated amplitude of the response was found in
animals exposed at 2,000 ppm or 2,400 ppm in one experiment and at approxi-
mately 1,500 or 2,000 ppm in another (estimated from a figure) but not at 500 or
1,000 ppm (estimated from a figure). For one of the experiments, the effect was
still present 4 weeks after exposure. Although it was not a subject in the Rebert
et al. (1995) study, it is known that exposure to other organic solvents can result in
permanent hearing loss from the destruction of cochlear hair cells. A reduction in
body weight gain was observed at 2,000 and 2,400 ppm. No information was
available on body weights of animals exposed at 1,500 ppm or less. Other effects
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Chlorobenzene
Grilli, S., G. Arfellini, A. Colacci, M. Mazzullo, and G. Prodi. 1985. In vivo and in vitro
covalent binding of chlorobenzene to nucleic acids. Jpn. J. Cancer Res. 76(8):745-
751.
Haworth, S., T. Lawlor, K. Mortelmans, W. Speck, and E. Zeiger. 1983. Salmonella
mutagenicity test results for 250 chemicals. Environ. Mutagen. (suppl. 1):3-142.
Hayes, W.C., T.S. Gushaw, K.A. Johnson, T.R. Hanley, J.H. Ouellette, and J.A. John.
1982. Monochlorobenzene: Inhalation Teratology Study in Rats and Rabbits. Dow
Chemical Company, Midland, MI (as cited in NTP 1985).
Hellman, B. 1993. NIOH and NIOSH Basis for an Occupational Health Standard:
Chlorobenzene. DHHS (NIOSH) 93-102. U.S. Department of Health and Human
Services, Public Health Service, Centers for Disease Control and Prevention, Na-
tional Institute for Occupational Safety and Health, Cincinnati, OH. January 1993
[online]. Available: http://www.cdc.gov/niosh/docs/93-102/pdfs/93-102.pdf [ac-
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IPCS (International Programme on Chemical Safety). 1991. Chlorobenzenes Other than
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Izmerov, N.F., N.M. Vasilenko, N.N. Semiletkina, and L.A. Timofiyevskaya. 1988.
Chlorobenzenes (Chlorobenzene, Dichlorobenzene, Trichlorobenzene). Scientific
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John, J.A., W.C. Hayes, T.R. Hanley, Jr., K.A. Johnson, T.S. Gushow, and K.S. Rao.
1984. Inhalation teratology study on monochlorobenzene in rats and rabbits. Toxi-
col. Appl. Pharmacol. 76(2):365-373.
Keskinova, D. 1968. The action of dimethylcyclodiazomethane in chlorobenzene solu-
tions on the mutation process in Actinomycetes antibioticus-400. Sov. Gen.
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113
Chlorobenzene
APPENDIX A
DERIVATION OF AEGLS VALUES FOR CHLOROBENZENE
Derivation of AEGL-1 Values
Key studies: Ogata, M., and Y. Shimada. 1983. Differences in
urinary monochlorobenzene metabolites between
rats and humans. Int. Arch. Occup. Environ.
Health 53(1):51-57.
Knecht, U., and H.J. Woitowitz. 2000. Human
toxicokinetics of inhaled monochlorobenzene:
Latest experimental findings regarding
re-evaluation of the biological tolerance value.
Int. Arch. Occup. Environ. Health 73(8):543-554.
Toxicity end point: Slight CNS effects (drowsiness, heavy feeling
in the head, and headache) and local irritation at
60 ppm (7 h with a 1-h break after 3 h) and no
effects at 10 ppm (8 h/day for 5 days). The latter
concentration was used as the point of departure.
Time scaling: None, because chlorobenzene concentrations in
blood reach a steady-state level within 1 h.
Uncertainty factors: 1 for interspecies differences
1 for intraspecies variability
Calculations:
10-min AEGL-1: Set equal to 8-h AEGL-1 value of 10 ppm
30-min AEGL-1: Set equal to 8-h AEGL-1 value of 10 ppm
1-h AEGL-1: Set equal to 8-h AEGL-1 value of 10 ppm
4-h AEGL-1: Set equal to 8-h AEGL-1 value of 10 ppm
8-h AEGL-1: 10 ppm
Derivation of AEGL-2 Values
Key study: UBTL (Utah Biomedical Test Laboratory). 1978.
Utah Biomedical Test Laboratory Report on
NIOSH Sponsored Inhalation Study for IDLH
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114 Acute Exposure Guideline Levels
Values (Final Report) with Cover Letter Dated
102291. Submitted by Shell Oil Company to U.S.
Environmental Protection Agency, Washington,
DC. EPA Document No. TSCATS 88-920000156.
Microfiche No. OTS 0534605.
Toxicity end point: Narcosis in rats and guinea pigs.
Time scaling: 2,990 ppm for 30 min was extrapolated across
time periods using the equation Cn × t = k, with
default values of n = 1 for extrapolation to 10-min
and n = 3 for extrapolation to 1-h values. The
4- and 8-h values were set equal to the 1-h value
because a steady-state chlorobenzene
concentration in blood is reached within 1 h
and for reasons of consistency with human data.
C3 × t = k:
k = (2,990 ppm)3 × 30 min = 8.02 × 1011 ppm-min
C1 × t = k:
k = 2,990 ppm × 30 min = 89,700 ppm-min
Uncertainty factors: 3 for interspecies differences
3 for intraspecies variability
Calculations:
[(8.02 × 1011 ppm-min) ÷ 10 min]1/3 ÷ 10 = 430
10-min AEGL-2:
ppm (rounded)
30-min AEGL-2: 2,990 ppm ÷ 10 = 300 ppm (rounded)
1-h AEGL-2: (89,700 ppm-min ÷ 60 min) ÷ 10 = 150 ppm
4-h AEGL-2: Set equal to 1-h AEGL-2 value of 150 ppm
8-h AEGL-2: Set equal to 1-h AEGL-2 value of 150 ppm
Derivation of AEGL-3 Values
Key study: UBTL (Utah Biomedical Test Laboratory). 1978.
Utah Biomedical Test Laboratory Report on
NIOSH Sponsored Inhalation Study for IDLH
Values (Final Report) with Cover Letter Dated
102291. Submitted by Shell Oil Company to U.S.
Environmental Protection Agency, Washington,
OCR for page 115
115
Chlorobenzene
DC. EPA Document No. TSCATS 88-920000156.
Microfiche No. OTS 0534605
Toxicity end point: No mortality in rats or guinea pigs.
Time scaling: 7,970 ppm for 30 min was extrapolated across
time periods using Cn × t = k, with default values
of n = 1 for extrapolation to 10-min and n = 3 for
extrapolation to 1-h values. The 4- and 8-h values
were set equal to the 1-h value because a steady-
state chlorobenzene concentration in blood is
reached in 1 h and for reasons of consistency
with AEGL-2 values.
C3 × t = k:
k = (7,970 ppm)3 × 30 min = 1.52 × 1013 ppm-min
C1 × t = k:
k = 7,970 ppm × 30 min = 239,100 ppm-min
Uncertainty factors: 3 for interspecies differences
3 for intraspecies variability
Calculations:
[(1.52 × 1013 ppm-min) ÷ 10 min]1/3 ÷ 10 = 1,100
10-min AEGL-3:
ppm (rounded)
30-min AEGL-3: 7,970 ppm ÷ 10 = 800 ppm (rounded)
1-h AEGL-3: (239,100 ppm-min ÷ 60 min) ÷ 10 = 400 ppm
(rounded)
4-h AEGL-3: Set equal to 1-h AEGL-3 value of 400 ppm
8-h AEGL-3: Set equal to 1-h AEGL-3 value of 400 ppm
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116 Acute Exposure Guideline Levels
APPENDIX B
CATEGORY PLOT FOR CHLOROBENZENE
Chemical
Chemical Toxicity - All
Chlorobenzene
100000,0000
10000,0000
Human - No effect
Human Discomfort
Human - Disabling
1000,0000
ppm
Animal - No effect
AEGL - 3
Animal - Discomfort
Animal Disabling
AEGL - 2
100,0000
Animal - Some
Lethality
Animal - Lethal
AEGL
AEGL - 1
10,0000
1,0000
0 60 120 180 240 300 360 420 480
Minutes
FIGURE B-1 Category plot of animal and human data and AEGL values for chloro-
benzene.
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117
Chlorobenzene
APPENDIX C
ACUTE EXPOSURE GUIDELINE LEVELS FOR CHLOROBENZENE
Derivation Summary for Chlorobenzene
AEGL-1 VALUES
10 min 30 min 1h 4h 8h
10 ppm 10 ppm 10 ppm 10 ppm 10 ppm
(47 mg/m3) (47 mg/m3) (47 mg/m3) (47 mg/m3) (47 mg/m3)
Key references:
Study 1: Ogata, M., and Y. Shimada. 1983 Differences in urinary
monochlorobenzene metabolites between rats and humans. Int. Arch. Occup.
Environ. Health 53(1):51-57.
Study 2: Knecht, U., and H.J. Woitowitz. 2000. Human toxicokinetics of inhaled
monochlorobenzene: Latest experimental findings regarding re-evaluation of the
biological tolerance value. Int. Arch. Occup. Environ. Health 73(8):543-554.
Test species/Strain/Number: Humans, 4 subjects (study 1), 8 subjects (study 2)
Exposure route/Concentrations/Durations: Study 1: inhalation, 60 ppm, 7-h exposure
with a 1-h break after 3 h; Study 2: inhalation, 10 ppm, 8 h/day for 5 days
Effects: Study 1: slight CNS effects (drowsiness, heavy feeling in the head, and
headache) and local irritation at 60 ppm; Study 2: no effects at 10 ppm.
End point/Concentration/Rationale: No discomfort effects at 10 ppm
Uncertainty factors/Rationale:
Total uncertainty factor: 1
Interspecies: 1, data are from a human study
Intraspecies: 1, effects at 60 ppm were very slight
Modifying factor: None
Animal-to-human dosimetric adjustment: Not relevant
Time scaling: None. No information on time dependency is available in the studies,
but the observed effects do not indicate a strong time dependency; this is also
supported by absorption data.
Data adequacy: The key studies were evaluations of the kinetics of chlorobenzene,
and were not designed to determine toxicity.
AEGL-2 VALUES
10 min 30 min 1h 4h 8h
430 ppm 300 ppm 150 ppm 150 ppm 150 ppm
(2,021 mg/m3) (1,410 mg/m3) (705 mg/m3) (705 mg/m3) (705 mg/m3)
Key reference: UBTL (Utah Biomedical Test Laboratory). 1978. Utah Biomedical
Test Laboratory Report on NIOSH Sponsored Inhalation Study for IDLH Values
(Continued)
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118 Acute Exposure Guideline Levels
AEGL-2 VALUES Continued
10 min 30 min 1h 4h 8h
430 ppm 300 ppm 150 ppm 150 ppm 150 ppm
(2,021 mg/m3) (1,410 mg/m3) (705 mg/m3) (705 mg/m3) (705 mg/m3)
(continued)
(Final Report) with Cover Letter Dated 102291. U.S. EPA/OPTS Public Files
OTS0534605. Submitted by Shell Oil Company to U.S. Environmental Protection
Agency, Washington, DC. EPA Document No. TSCATS 88-920000156. Microfiche
No. OTS 0534605.
Test species/Strain/Number: Rats and guinea pigs, strains unknown, five per sex
per species.
Exposure route/Concentrations/Durations: Inhalation, 2,990, 5,850, or 7,970 ppm
for 30 min; 14-day observation.
Effects:
2,990 ppm: Slight ocular and nasal irritation
5,850 ppm: Narcosis and impaired ability to escape
7,970 ppm: No deaths; ataxia and narcosis
End point/Concentration/Rationale: No narcosis at 2,990 ppm for 30 min; no
animals suffered from impaired ability to escape.
Uncertainty factors/Rationale:
Total uncertainty factor: 10 (a larger uncertainty factor would lead to AEGL-2
values that conflict with human data)
Interspecies: 3, data were comparable for rats and guinea pigs suggesting no large
interspecies differences, and the critical effect is CNS depression.
Intraspecies: 3, interindividual variability for CNS depression by comparable gases
generally will not be greater than a factor of 2 or 3.
Modifying factor: None
Animal-to-human dosimetric adjustment: None
Time scaling: Cn × t = k; default values of n = 3 for 10-min value and n = 1 for
60-min value. AEGL-2 values for 4 and 8 h are set equal to the 1-h value because
chlorobenzene concentrations in blood reach a steady-state within 1 h and its
elimination is rapid. Time scaling would result in 4- and 8-h AEGL-2 values that
would conflict with human data.
Data adequacy: Only one study (30-min exposures at three concentrations) aimed
at identifying an immediately dangerous to life and health value.
AEGL-3 VALUES
10 min 30 min 1h 4h 8h
1,100 ppm 800 ppm 400 ppm 400 ppm 400 ppm
(5,170 mg/m3) (3,760 mg/m3) (1,880 mg/m3) (1,880 mg/m3) (1,880 mg/m3)
Key reference: UBTL (Utah Biomedical Test Laboratory). 1978. Utah Biomedical
Test Laboratory Report on NIOSH Sponsored Inhalation Study for IDLH Values
(Continued)
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119
Chlorobenzene
AEGL-3 VALUES Continued
10 min 30 min 1h 4h 8h
1,100 ppm 800 ppm 400 ppm 400 ppm 400 ppm
(5,170 mg/m3) (3,760 mg/m3) (1,880 mg/m3) (1,880 mg/m3) (1,880 mg/m3)
(Final Report) with Cover Letter Dated 102291. Submitted by Shell Oil Company
to U.S. Environmental Protection Agency, Washington, DC. EPA Document No.
TSCATS 88-920000156. Microfiche No. OTS 0534605
Test species/Strain/Number: Rats and guinea pigs, strains unknown, five per sex
per species.
Exposure route/Concentrations/Durations: Inhalation, 2,990, 5,850, or 7,970 ppm
for 30 min; 14-day observation.
Effects:
2,990 ppm: Slight ocular and nasal irritation
5,850 ppm: Narcosis and impaired ability to escape
7,970 ppm: No deaths; ataxia and narcosis
End point/Concentration/Rationale: No deaths after 30-min exposure at 7,970 ppm.
Uncertainty factors/Rationale:
Total uncertainty factor: 10 (a larger factor would lead to AEGL-3 values that
would conflict with AEGL-2 values)
Interspecies: 3, data were comparable for rats and guinea pigs suggesting no
large interspecies differences, and the critical effect is CNS depression.
Intraspecies: 3, interindividual variability for CNS depression by comparable
gases generally will not be greater than a factor of 2 or 3.
Modifying factor: None
Animal-to-human dosimetric adjustment: None
Time scaling: Cn × t = k; default values of n = 3 for 10-min value and n = 1 for
1-h value. AEGL-3 values for 4- and 8-h are set equal to the 1-h value because
chlorobenzene concentrations in blood reach a steady-state within 1 h and its
elimination is rapid. Furthermore, time scaling would result in 4- and 8-h
AEGL-3 values that would conflict with AEGL-2 values and human data.
Data adequacy: Sufficient
